Hemoglobin (Hb) represents more than 90 percent of the protein of the mature erythrocyte and Hb synthesis represents more than 90 percent of the protein synthesis of the reticulocyte. One model that may lend insight into this extreme commitment is found in goats and certain sheep. When anemic, these animals replace HbA with HbC; HbA reappears upon recovery from anemia. HbA and HbC differ in the beta chain. Studies with fluorescent antibodies strongly suggest that both Hbs are present in the same erythrocyte during the switch. Studies suggesting exchange of alpha chains common to the two Hbs tentatively support this conclusion. We have also provided stronger immunochemical confirmation that the switch is not a clonal phenomenon. The gene excision hypothesis (Kabat, D., 1972. Gene selection in hemoglobin and antibody-synthesizing cells. Science, 175: 134-140) predicts that red cells with all three types of beta chains will not be found in animals heterozygous for a beta variant and switching to HbC production. We also propose to test this prediction with immunochemical methods. If these studies prove intractable with immunochemical procedures, we propose to use the followwng methods or a combination thereof: (1) electrophoresis or isoelectric focusing of the contents of individual erythrocytes and (2) specific elution of Hb(s) from erythrocyte smears. The proposed studies constitute major steps in an attempt both to understand the mechanism of switches in gene expression and to gain the ability to prevent or reverse such switching.